The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence.
We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.
Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Duesseldorf, Germany. ingmar.bruns@med.uni-duesseldorf.de
%0 Journal Article
%1 Bruns2009
%A Bruns, I.
%A Czibere, A.
%A Fischer, J. C.
%A Roels, F.
%A Cadeddu, R-P.
%A Buest, S.
%A Bruennert, D.
%A Huenerlituerkoglu, A. N.
%A Stoecklein, N. H.
%A Singh, R.
%A Zerbini, L. F.
%A Jäger, M.
%A Kobbe, G.
%A Gattermann, N.
%A Kronenwett, R.
%A Brors, B.
%A Haas, R.
%D 2009
%J Leukemia
%K Adhesion; Analysis; Antibody Array BCR-ABL Cell Cells, Cells; Chain Chronic, Differentiation; Expression Fluorescent Gene Hematopoietic Humans; Leukemia, Leukemic, Messenger, Movement; Myelogenous, Myeloid Neoplastic Oligonucleotide Polymerase Positive, Profiling; Progenitor Proliferation; RNA, Reaction Regulation, Reverse Sequence Stem Technique; Transcriptase genetics/pathology; genetics; metabolism; pathology;
%N 5
%P 892--899
%R 10.1038/leu.2008.392
%T The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence.
%U http://dx.doi.org/10.1038/leu.2008.392
%V 23
%X We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.
@article{Bruns2009,
__markedentry = {[bbrors:6]},
abstract = {We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Bruns, I. and Czibere, A. and Fischer, J. C. and Roels, F. and Cadeddu, R-P. and Buest, S. and Bruennert, D. and Huenerlituerkoglu, A. N. and Stoecklein, N. H. and Singh, R. and Zerbini, L. F. and J{\"{a}}ger, M. and Kobbe, G. and Gattermann, N. and Kronenwett, R. and Brors, B. and Haas, R.},
biburl = {https://www.bibsonomy.org/bibtex/2eff6cd9fbf47b92b9a784f205b75b46b/bbrors},
doi = {10.1038/leu.2008.392},
institution = {Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Duesseldorf, Germany. ingmar.bruns@med.uni-duesseldorf.de},
interhash = {794dd680091004e6e2dc46de45387095},
intrahash = {eff6cd9fbf47b92b9a784f205b75b46b},
journal = {Leukemia},
keywords = {Adhesion; Analysis; Antibody Array BCR-ABL Cell Cells, Cells; Chain Chronic, Differentiation; Expression Fluorescent Gene Hematopoietic Humans; Leukemia, Leukemic, Messenger, Movement; Myelogenous, Myeloid Neoplastic Oligonucleotide Polymerase Positive, Profiling; Progenitor Proliferation; RNA, Reaction Regulation, Reverse Sequence Stem Technique; Transcriptase genetics/pathology; genetics; metabolism; pathology;},
language = {eng},
medline-pst = {ppublish},
month = May,
number = 5,
owner = {bbrors},
pages = {892--899},
pii = {leu2008392},
pmid = {19158832},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence.},
url = {http://dx.doi.org/10.1038/leu.2008.392},
volume = 23,
year = 2009
}